Patient-Derived In Vitro Models of Microglial Function and Synaptic Engulfment in Schizophrenia

Multiple lines of evidence implicate dysregulated microglia-mediated synaptic pruning in the pathophysiology of schizophrenia. In vitro human cellular studies represent a promising means of pursuing this hypothesis, com-plementing efforts with animal models and postmortem human data while addressing their limitations. The challenges in culturing homogeneous populations of cells derived from postmortem or surgical biopsy brain material from pa-tients, and their limited availability, has led to a focus on differentiation of induced pluripotent stem cells. These methods too have limitations, in that they disrupt the epigenome and can demonstrate line-to-line variability due in part to extended time in culture, partial reprogramming, and/or residual epigenetic memory from the cell source, yielding large technical artifacts. Yet another strategy uses direct transdifferentiation of peripheral mononuclear blood cells, or umbilical cord blood cells, to microglia-like cells. Any of these approaches can be paired with patient-derived synaptosomes from differentiated neurons as a simpler alternative to co-culture. Patient-derived microglia models may facilitate identification of novel modulators of synaptic pruning and identification of biomarkers that may allow more targeted early interventions.

Automated summary

Multiple lines of evidence suggest that dysregulated microglia-mediated synaptic pruning plays a key role in the pathophysiology of schizophrenia. In vitro human cellular studies provide a promising approach to investigate this hypothesis, complementing animal models and postmortem human data. Different methods have their limitations, but patient-derived microglia models may facilitate the identification of novel regulators of synaptic pruning and biomarkers for targeted early interventions.